Titrimetric and spectrophotometric methods are described for the determination of oxcarbazepine (OXC) in bulk drug and in tablets. The methods use N-bromosuccinimide (NBS) and bromopyrogallol red (BPR) as reagents. In titrimetry (method A), an acidified solution of OXC is titrated directly with NBS using methyl orange as indicator. Spectrophotometry (method B) involves the addition of known excess of NBS to an acidified solution of OXC followed by the determination of the unreacted NBS by reacting with BPR and measuring the absorbance of the unreacted dye at 460 nm. Titrimetry allows the determination of 6-18 mg of OXC and follows a reaction stoichiometry of 1 : 1 (OXC : NBS), whereas spectrophotometry is applicable over the concentration range of 0.8-8.0 μg mL(-1). Method B with a calculated molar absorptivity of 2.52 × 10(4) L mol(-1) cm(-1) is the most sensitive spectrophotometric method ever developed for OXC. The optical characteristics such as limits of detection (LOD), quantification (LOQ), and Sandell's sensitivity values are also reported for the spectrophotometric method. The accuracy and precision of the methods were studied on intraday and interday basis. The methods described could usefully be applied to routine quality control of tablets containing OXC. No interference was observed from common pharmaceutical adjuvants. Statistical comparison of the results with a reference method shows an excellent agreement and indicates no significant difference in accuracy and precision. The reliability of the methods was further ascertained by recovery studies in standard addition procedure.

Epilepsy is a chronic disease occurring in approximately 1.0% of the world's population. About 30% of the epileptic patients treated with availably antiepileptic drugs (AEDs) continue to have seizures and are considered therapy-resistant or refractory patients. The ultimate goal for the use of AEDs is complete cessation of seizures without side effects. Because of a narrow therapeutic index of AEDs, a complete understanding of its clinical pharmacokinetics is essential for understanding of the pharmacodynamics of these drugs. These drug concentrations in biological fluids serve as surrogate markers and can be used to guide or target drug dosing. Because early studies demonstrated clinical and/or electroencephalographic correlations with serum concentrations of several AEDs, It has been almost 50 years since clinicians started using plasma concentrations of AEDs to optimize pharmacotherapy in patients with epilepsy. Therefore, validated analytical method for concentrations of AEDs in biological fluids is a necessity in order to explore pharmacokinetics, bioequivalence and TDM in various clinical situations. There are hundreds of published articles on the analysis of specific AEDs by a wide variety of analytical methods in biological samples have appears over the past decade. This review intends to provide an updated, concise overview on the modern method development for monitoring AEDs for pharmacokinetic studies, bioequivalence and therapeutic drug monitoring.

In the past twenty years, 14 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. In general, the clinical utility of therapeutic drug monitoring has not been established in clinical trials for these new anticonvulsants, and clear guidelines for drug monitoring have yet to be defined. The antiepileptic drugs with the strongest justifications for drug monitoring are lamotrigine, oxcarbazepine, stiripentol, and zonisamide. Stiripentol and tiagabine are strongly protein bound and are candidates for free drug monitoring. Therapeutic drug monitoring has lower utility for gabapentin, pregabalin, and vigabatrin. Measurement of salivary drug concentrations has potential utility for therapeutic drug monitoring of lamotrigine, levetiracetam, and topiramate. Therapeutic drug monitoring of the new antiepileptic drugs will be discussed in managing patients with epilepsy.

A rapid and reliable analytical method suitable for the simultaneous determination of the antiepileptic drug, oxcarbazepine and its metabolites in human plasma and saliva by means of liquid chromatography with diode array detection (DAD) has been developed. Oxcarbazepine and its metabolites (10,11-dihydro-10-hydroxycarbamazepine, trans-10,11-dihydro-10,11-dihydroxycarbamazepine and 3-hydroxycarbamazepine) were baseline separated within 6.5min on a reversed-phase C18 column with a phosphate buffer-acetonitrile-triethylamine mixture as the mobile phase. The DAD detector was set at 240nm. A sample preparation method for biological samples using a microextraction by packed sorbent technique has been implemented, employing a C18 sorbent inserted into a microvolume syringe and using only a small volume (25muL) of plasma or saliva. The extraction yield values were satisfactory for all analytes (>86.5%) as well as the precision data, which were always in the low percentage of relative standard deviation values (<4.6%). The method was successfully applied to both plasma and saliva samples drawn from psychiatric and neurological patients undergoing treatment with oxcarbazepine (Tolep((R))) tablets.

A sensitive, simple and selective spectrofluorimetric method was developed for the determination of Lamotrigine (LMT) in pharmaceutical formulations and biological fluids. The method is based on reaction of LMT with o-phthalaldehyde in presence of 2-mercaptoethanol in borate buffer of pH 9.8 to yield a highly fluorescent derivative that is measured at 448 nm after excitation at 337 nm. The different experimental parameters affecting the development and stability of the reaction product were carefully studied and optimized. The fluorescence-concentration plot was rectilinear over the range of 0.1-1.0 microg ml(-1) with lower limit of detection (LOD) 0.02 microg ml(-1) and limit of quantification (LOQ) 0.06 microg ml(-1) respectively. The proposed method was successfully applied to the the analysis of commercial tablets. Statistical comparison of the results obtained by the proposed and reference method revealed no significant difference in the performance of the two methods regarding the accuracy and precision respectively. The proposed method was further extended to the in-vitro and in-vivo determination of the drug in spiked and real human plasma. The mean percentage recoveries in spiked and real human plasma (n = 3) were 95.78 +/- 1.37 and 90.93 +/- 2.34 respectively. Interference arising from co-administered drugs was also studied. A proposal for the reaction pathway with o-phthalaldehyde was postulated.

Therapeutic drug monitoring of antiepileptic drugs (AEDs) is important in maximizing the therapeutic response while minimizing the adverse effects. High-performance liquid chromatography (HPLC) is the most commonly used technique for this purpose. Recently, commercial monolithic columns were introduced, which consist of a single rod of fused silica or polymer. The objective of this work was to develop a simple and fast method to quantify 10 commonly measured AEDs or metabolites [carbamazepine, carbamazepine-10,11-epoxide, felbamate, lamotrigine, 10,11-dihydro-10-hydroxy-carbamazepine (active metabolite of oxcarbazepine), pentobarbital, phenobarbital, phenytoin, primidone, and zonisamide] in serum/plasma by HPLC using a reverse-phase monolithic column. Serum/heparin plasma (100 microL) was mixed with an internal standard solution (5-ethyl-5-p-tolylbarbituric acid in methanol, 250 microL). After centrifugation at 15,500 g for 10 minutes, 15 microL of supernatant was injected into a monolithic column. The analytes were eluted with an isocratic solution of 0.1 M, pH 6.5, phosphate buffer:methanol:acetonitrile (77:20:3), monitored at 210 nm. The chromatography time was 16 minutes. The method was linear from 0.4-4.9 to 21.2-190.9 microg/mL depending on the analytes with analytical recovery of 80%-114%. The inter- and intra-assay coefficients of variation were <8% in 3 levels of serum-based controls for all the analytes. No significant carryover was observed. Commercial controls containing >100 therapeutic drugs and common endogenous substances were tested and showed no interference. Comparison studies for 6 AEDs or metabolites were performed against commercial HPLC methods. Three AEDs were compared with Food and Drug Administration-approved immunoassays. All comparisons had R > 0.96 with slope ranging from 0.86 to 1.20. This is a simple and fast HPLC method suitable for measuring the 10 AEDs or metabolites. The use of the monolithic column resulted in increased sensitivity, better resolution, and a shorter analytical time compared with a regular C18 column.

Bipolar disorder (BD) is a long-term illness with mood swings which are characterized by recurrent episodes of mania/hypomania and depression, with variable interpolations of relatively asymptomatic periods, called euthymic, in which, however, some psychopathological symptoms may persist. Although mood stabilizers, such as lithium, are the first-line treatment for the prevention of new BD episodes, combination therapy has become the standard of care for BD patients. Besides lithium, the use of a mood stabilizer along with an atypical antipsychotic is recommended in many patients. Recently, atypical antipsychotics (quetiapine, olanzapine, risperidone and aripiprazole) and antiepileptic agents (valproate, lamotrigine and oxcarbazepine) are increasingly used as mood stabilizers. To reduce side effects and optimize treatment it is important to perform accurate monitoring of drug blood levels in these patients, who are often treated with multiple drugs. Therapeutic drug monitoring (TDM) is in fact a powerful tool that, starting from clinical-chemical correlation data, allows to tailor-cut treatment to the specific needs of individual patients; hence the need to have reliable analytical methods available for the determination of plasma levels of drugs and their metabolites. Analyses of biological samples are mainly carried out using high-performance liquid chromatography (HPLC) coupled with different detectors, capillary electrophoresis and gas-chromatography. Various procedures are employed to remove biological interferences before analyzing the samples. This review focuses on currently available analytical TDM methods for atypical antipsychotics and antiepileptic agents used in the treatment of patients with bipolar disorder. Advantages and limitations of the various analytical methods will be reviewed and discussed, together with an evaluation of the role of TDM.

INTRODUCTION p-Chloroaniline is more potent at producing methemoglobin than aniline in animal models. This case highlights the clinical presentation of an inhalation exposure to p-chloroaniline and associated laboratory analysis. An in-vitro study evaluating the metabolism of p-chloroaniline in human hepatocytes was undertaken to evaluate the metabolic fate more closely. CASE PRESENTATION A 20 year-old man was working at a chemical waste plant when he developed dizziness, abdominal pain, and nausea. The exam was remarkable for coma, tachycardia, cyanosis, and pulse oximetry of 75%. Arterial blood gases showed a pH 7.38, pCO(2) 41 mmHg, pO(2) 497 mmHg, bicarbonate 24 mEq/L and methemoglobin 69%. Methylene blue administration led to complete recovery without sequelae. p-Chloroaniline was later identified as the chemical involved. He denied direct contact with the chemical, but was not wearing a dust mask or respirator. GC/MS confirmed p-chloroaniline and metabolites in the patient's urine. METHODS Human hepatocytes were incubated with 100 microM p-chloroaniline for 24 hours, in both rifampicin- and vehicle only-treated cells. The cell culture medium was collected for GC/MS analysis for p-chloroaniline metabolites. RESULTS Similar to the patient sample, both p-chloroaniline and p-chloroacetanilide were identified by GC/MS in hepatocytes incubated with p-chloroaniline. Neither p-chloroaniline incubated in empty cell culture nor direct GC/MS injection of p-chloroaniline generated any p-chloroacetanilide via non-enzymatic degradation. DISCUSSION/CONCLUSION The seemingly innocuous dermal and inhalation exposure to p-chloroaniline dust can lead to life-threatening methemoglobinemia. The diagnosis can be confirmed with GC/MS analysis of the patient's urine, searching for p-chloroaniline and its primary metabolite p-chloroacetanilide.

A high-performance liquid chromatography assay with ultraviolet detection was developed for the simultaneous determination of the anti-epileptic drugs lamotrigine, carbamazepine and zonisamide in human plasma and serum. Lamotrigine, carbamazepine, zonisamide and the internal standard chloramphenicol were extracted from serum or plasma using liquid-liquid extraction under alkaline conditions into an organic solvent. The method was linear in the range 1-30 microg/mL for lamotrigine, 2-20 microg/mL for carbamazepine, and 1-40 microg/mL for zonisamide. Within- and between-run precision studies demonstrated coefficient of variation <10% at all tested concentrations. Other anti-epileptic medications tested did not interfere with the assay. The method is appropriate for determining lamotrigine, carbamazepine and zonisamide serum or plasma concentrations for therapeutic monitoring.

BACKGROUND Laboratory tests for routine drug of abuse and toxicology (DOA/Tox) screening, often used in emergency medicine, generally utilize antibody-based tests (immunoassays) to detect classes of drugs such as amphetamines, barbiturates, benzodiazepines, opiates, and tricyclic antidepressants, or individual drugs such as cocaine, methadone, and phencyclidine. A key factor in assay sensitivity and specificity is the drugs or drug metabolites that were used as antigenic targets to generate the assay antibodies. All DOA/Tox screening immunoassays can be limited by false positives caused by cross-reactivity from structurally related compounds. For immunoassays targeted at a particular class of drugs, there can also be false negatives if there is failure to detect some drugs or their metabolites within that class. METHODS Molecular similarity analysis, a computational method commonly used in drug discovery, was used to calculate structural similarity of a wide range of clinically relevant compounds (prescription and over-the-counter medications, illicit drugs, and clinically significant metabolites) to the target ('antigenic') molecules of DOA/Tox screening tests. These results were compared with cross-reactivity data in the package inserts of immunoassays marketed for clinical testing. The causes for false positives for phencyclidine and tricyclic antidepressant screening immunoassays were investigated at the authors' medical center using gas chromatography/mass spectrometry as a confirmatory method. RESULTS The results illustrate three major challenges for routine DOA/Tox screening immunoassays used in emergency medicine. First, for some classes of drugs, the structural diversity of common drugs within each class has been increasing, thereby making it difficult for a single assay to detect all compounds without compromising specificity. Second, for some screening assays, common 'out-of-class' drugs may be structurally similar to the target compound so that they account for a high frequency of false positives. Illustrating this point, at the authors' medical center, the majority of positive screening results for phencyclidine and tricyclic antidepressants assays were explained by out-of-class drugs. Third, different manufacturers have adopted varying approaches to marketed immunoassays, leading to substantial inter-assay variability. CONCLUSION The expanding structural diversity of drugs presents a difficult challenge for routine DOA/Tox screening that limit the clinical utility of these tests in the emergency medicine setting.

BACKGROUND Immunoassays used for routine drug of abuse (DOA) and toxicology screening may be limited by cross-reacting compounds able to bind to the antibodies in a manner similar to the target molecule(s). To date, there has been little systematic investigation using computational tools to predict cross-reactive compounds. METHODS Commonly used molecular similarity methods enabled calculation of structural similarity for a wide range of compounds (prescription and over-the-counter medications, illicit drugs, and clinically significant metabolites) to the target molecules of DOA/toxicology screening assays. We used various molecular descriptors (MDL public keys, functional class fingerprints, and pharmacophore fingerprints) and the Tanimoto similarity coefficient. These data were then compared with cross-reactivity data in the package inserts of immunoassays marketed for in vitro diagnostic use. Previously untested compounds that were predicted to have a high probability of cross-reactivity were tested. RESULTS Molecular similarity calculated using MDL public keys and the Tanimoto similarity coefficient showed a strong and statistically significant separation between cross-reactive and non-cross-reactive compounds. This result was validated experimentally by discovery of additional cross-reactive compounds based on computational predictions. CONCLUSIONS The computational methods employed are amenable toward rapid screening of databases of drugs, metabolites, and endogenous molecules and may be useful for identifying cross-reactive molecules that would be otherwise unsuspected. These methods may also have value in focusing cross-reactivity testing on compounds with high similarity to the target molecule(s) and limiting testing of compounds with low similarity and very low probability of cross-reacting with the assay.

We report a rare case of intentional overdose of phenylbutazone in a 15-yr-old female. The patient exhibited symptoms of phenylbutazone toxicity and the presence of the drug was confirmed by gas chromatography mass-spectrometry (GC-MS) analysis of the initial urine sample. The patient underwent plasmapheresis to remove the drug from the circulation. Semiquantitation of sequential serum samples by GC-MS revealed elimination of phenylbutazone by day 5 of admission at which time the plasmapheresis was discontinued. Elevated blood urea nitrogen (BUN) and creatinine returned to normal. Analysis of biomarkers for liver necrosis and regeneration in sequential serum samples revealed the restoration of normal liver function by day 5. This case further confirms our previous observations that biomarkers for liver necrosis and regeneration can predict the outcome of patients with liver damage due to toxins.

The human pregnane X receptor (PXR) is a ligand dependent transcription factor that can be activated by structurally diverse agonists including steroid hormones, bile acids, herbal drugs, and prescription medications. PXR regulates the transcription of several genes involved in xenobiotic detoxification and apoptosis. Activation of PXR has the potential to initiate adverse effects by altering drug pharmacokinetics or perturbing physiological processes. Hence, more reliable prediction of PXR activators would be valuable for pharmaceutical drug discovery to avoid potential toxic effects. Ligand- and protein structure-based computational models for PXR activation have been developed in several studies. There has been limited success with structure-based modeling approaches to predict human PXR activators, which can be attributed to the large and promiscuous site of this protein. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning that use appropriate descriptors to account for the diversity of the ligand classes that bind to PXR. These combined computational approaches using molecular shape information may assist scientists to more confidently identify PXR activators. This chapter reviews the various ligand and structure based methods undertaken to date and their results.

ABSTRACT: BACKGROUND: Hepatitis B virus (HBV) is a common cause of viral hepatitis with significant health complications including cirrhosis and hepatocellular carcinoma. Assays for hepatitis B surface antigen (HBsAg) are the most frequently used tests to detect HBV infection. Vaccination for HBV can produce transiently detectable levels of HBsAg in patients. However, the time course and duration of this effect is unclear. The objective of this retrospective study was to clarify the frequency and duration of transient HBsAg positivity following vaccination against HBV. METHODS: The electronic medical record at an academic tertiary care medical center was searched to identify all orders for HBsAg within a 17 month time period. Detailed chart review was performed to identify all patients who were administered HBV vaccine within 180 days prior to HBsAg testing and also to ascertain likely cause of weakly positive (grayzone) results. RESULTS: During the 17 month study period, 11,719 HBsAg tests were ordered on 9,930 patients. There were 34 tests performed on 34 patients who received HBV vaccine 14 days or less prior to HBsAg testing. Of these 34 patients, 11 had grayzone results for HBsAg that could be attributed to recent vaccination. Ten of the 11 patients were renal dialysis patients who were receiving HBsAg testing as part of routine and ongoing monitoring. Beyond 14 days, there were no reactive or grayzone HBsAg tests that could be attributed to recent HBV vaccination. HBsAg results reached a peak COI two to three days following vaccination before decaying. Further analysis of all the grayzone results within the 17 month study period (43 results out of 11,719 tests) revealed that only 4 of 43 were the result of true HBV infection as verified by confirmatory testing. CONCLUSIONS: Our study confirms that transient HBsAg positivity can occur in patients following HBV vaccination. The results suggest this positivity is unlikely to persist beyond 14 days post-vaccination. Our study also demonstrates that weakly positive HBsAg results often do not reflect actual HBV infection, underscoring the importance of confirmatory testing. This study also emphasizes that vaccination-induced HBsAg positives occur most commonly in hemodialysis patients.

BACKGROUND: A 21-year old female suffered a cardiac arrest after a one week history of viral illness later shown to be caused by influenza B. The patient required extended cardiopulmonary resuscitation and had further complications including compartment syndrome. METHODS: Plasma myoglobin concentration was measured using the Roche Diagnostics electrochemiluminescent myoglobin assay. RESULTS: The myoglobin concentration was 205,590μg/l in an undiluted specimen, consistent with severe rhabdomyolysis. Subsequent myoglobin concentrations measured two days later showed dramatic decreases to approximately 1000μg/l, raising suspicion of a hook effect. Dilution and re-analysis of the specimens revealed that the actual myoglobin concentrations were >395,000μg/l, with one specimen possessing an estimated myoglobin concentration of >600,000μg/l. Interestingly, three specimens from this patient did not show evidence of hook effect, with undiluted specimens producing myoglobin concentrations as high as 284,000μg/l. Retrospective analysis of myoglobin results over an 8-year period did not reveal other cases with suspicion of hook effect. The case patient had the highest myoglobin concentrations out of 7301 specimens. CONCLUSIONS: This case illustrates that while the Roche myoglobin assay has a very wide dynamic range, hook effect can occur with extremely high concentrations of plasma myoglobin.

Lamotrigine (6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine), a phenyltriazine anticonvulsant, is a newer anti-epileptic drug. A profile of this drug substance is provided in this chapter and includes physical characteristics of Lamotrigine (e.g. Uv/Vis, IR, NMR and mass spectra). Details regarding the stability of Lamotrigine in the solid-state and solution-phase are presented and methods of analysis (compendial and literature) are summarized. Furthermore, an account of the pharmacokinetics (ADME) and synthesis of Lamotrigine are presented.

HASH(0x2b989431e0e0)

We present an implementation of a method we previously reported allowing the newer antiepileptic drugs (AEDs) rufinamide (RFN) and zonisamide (ZNS) to be simultaneously determined with lamotrigine (LTG), oxcarbazepine's (OXC) main active metabolite monohydroxycarbamazepine (MHD) and felbamate (FBM) in plasma of patients with epilepsy using high performance liquid chromatography (HPLC) with UV detection. Plasma samples (250 microL) were deproteinized by 1 mL acetonitrile spiked with citalopram as internal standard (I.S.). HPLC analysis was carried out on a Synergi 4 microm Hydro-RP, 250 mm x 4.6 mm I.D. column. The mobile phase was a mixture of potassium dihydrogen phosphate buffer (50 mM, pH 4.5), acetonitrile and methanol (65:26.2:8.8, v/v/v) at an isocratic flow rate of 0.8 mL/min. The UV detector was set at 210 nm. The chromatographic run lasted 19 min. Commonly coprescribed AEDs did not interfere with the assay. Calibration curves were linear for both AEDs over a range of 2-40 microg/mL for RFN and 2-80 microg/mL for ZNS. The limit of quantitation was 2 microg/mL for both analytes and the absolute recovery ranged from 97% to 103% for RFN, ZNS and the I.S. Intra- and interassay precision and accuracy were lower than 10% at all tested concentrations. The present study describes the first simple and validated method for RFN determination in plasma of patients with epilepsy. By grouping different new AEDs in the same assay the method can be advantageous for therapeutic drug monitoring (TDM).

A high-performance liquid chromatography assay with ultraviolet detection was developed for the simultaneous determination of the anti-epileptic drugs lamotrigine, carbamazepine and zonisamide in human plasma and serum. Lamotrigine, carbamazepine, zonisamide and the internal standard chloramphenicol were extracted from serum or plasma using liquid-liquid extraction under alkaline conditions into an organic solvent. The method was linear in the range 1-30 microg/mL for lamotrigine, 2-20 microg/mL for carbamazepine, and 1-40 microg/mL for zonisamide. Within- and between-run precision studies demonstrated coefficient of variation <10% at all tested concentrations. Other anti-epileptic medications tested did not interfere with the assay. The method is appropriate for determining lamotrigine, carbamazepine and zonisamide serum or plasma concentrations for therapeutic monitoring.

A new generation of antiepileptic drugs (AEDs) has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide. The newer AEDs in general have more predictable pharmacokinetics than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined 'therapeutic range', representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution, since many patients are optimally treated when they have serum concentrations below or above the suggested range. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs, although this is partially based on the lack of documented correlation between serum concentration and drug effects. Nevertheless, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of 'individual reference concentrations' based on intra-individual comparisons of drug serum concentrations. With this concept, TDM may be indicated regardless of the existence or lack of a well-defined therapeutic range.The ten newer AEDs all have different pharmacological properties, and therefore, the usefulness of TDM for these drugs has to be assessed individually. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. The mode of action of the other new AEDs would not preclude the applicability of TDM. For the prodrug oxcarbazepine, TDM is also useful, since the active metabolite licarbazepine is measured.For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the pharmacokinetic variability of all renally eliminated AEDs. For those of the newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs. Therefore, TDM is likely to be useful in many clinical settings for the newer AEDs. The purpose of the present review is to discuss individually the potential value of TDM of these newer AEDs, with emphasis on pharmacokinetic variability.

This article describes a rapid high-performance liquid chromatographic (HPLC) method for the measurement of the primary metabolite of oxcarbazepine. Following a simple precipitation step, 10,11,-dihydro-10-hydroxy-5H-dibenzo(b,f)azepine-5-carboxamide is quantitated (5-60 microg/mL) by analysis on an HPLC-UV system. The instrument time is less than 5 min per injection, an improvement over most published methods. The assay's limit of quantitation, linearity, imprecision, and accuracy adequately cover the therapeutic range for appropriate patient monitoring. In comparison to other published methods, this procedure would be of interest to clinical laboratories because it employs a precipitation step for sample preparation, instead of conventional yet time-consuming solid-phase extraction.

A simple and rapid high performance liquid chromatographic method for determination of efavirenz in human plasma was developed. The method involved extraction of sample with ethyl acetate and analysis using a reversed-phase C(18) column (150 mm) with UV detection. The assay was linear from 0.0625 to 10.0 microg/ml. The method was specific for efavirenz estimation and the drug was stable in plasma up to one month at -20 degrees C. The average recovery of efavirenz from plasma was 101%. Due to its simplicity, the assay can be used for pharmacokinetic studies and therapeutic drug monitoring of efavirenz.

A simple HPLC assay to determine plasma concentration of tipranavir is presented. A liquid/liquid extraction of the drugs in ethyl acetate/hexane from 250muL of plasma is followed by a reversed phase isocratic HPLC assay with UV detection at 205nm. The imprecision and inaccuracy are lower than 10%, the low limit of quantitation is 0.4mg/L. Thus, this method can be used for therapeutic drug monitoring of tipranavir in HIV infected patients.

BACKGROUND The principles of epilepsy management are accurate diagnosis coupled with education, lifestyle advice, and drug therapy. There are a large number of anti-epileptic drugs now available. OBJECTIVE This article deals with initial treatment, the role of the newer agents, and practical issues such as monitoring of therapy and the use of generic drugs. The difficult issues of when to stop therapy and management of epilepsy in pregnancy are highlighted. DISCUSSION Accurate seizure and syndrome diagnosis determines the optimal choice of medication. In most patients with new onset epilepsy, seizures can be easily controlled with lifestyle modification and medication. In general, valproate is first line treatment for generalised epilepsy and carbamazepine for partial epilepsies. New anti-epileptic drugs offer benefits in patients who are not controlled or intolerant of the older agents. Monitoring of therapy is primarily clinical; not necessarily requiring testing for serum levels or other blood tests.

A rapid, selective and sensitive isocratic reversed-phase HPLC method for the simultaneous determination of oxcarbazepine, its main metabolites (mono and dihydroxycarbazepine), lamotrigine, carbamazepine and carbamazepine-epoxide in plasma samples has been implemented. Analytes were extracted on solid-phase cartridges (SPE) and chromatographic separation was achieved on a Zorbax SB-CN column. The chromatographic peak area ratio based on UV absorbency at 214 nm was used for quantitative analysis. This HPLC method has been successfully used for routine evaluation to monitor plasma concentrations in epileptic patients referred to our institute and for pharmacokinetic studies regarding patients cotreated with drugs inducing or inhibiting OXC metabolism.